We believe that aged lymphocytes may be less susceptible to HIV-1-mediated cell death and may serve as a reservoir promoting virion production. Given T cell phenotypic alterations that have been observed in various chronic inflammatory disease states and aging, we believe that a similar systemic Th2 polarization may occur in circulating T cells of elderly subjects making them more susceptible to HIV-1 disease. Based on these findings, we are examining various parameters of HIV-1-mediated signaling, replication and immunopathogenesis using young and aged mononuclear cells and T lymphocytes. Additional studies are being performed examining alterations in the circulating homocysteine, vitamin B12, folate, and red blood cell folate levels in these subjects to determine if there are any age- and HIV-related changes in these subjects and any possible correlations with immune phenotypes and cellular apoptosis. In addition, we have continued our research studying the basic biology of the chemokine co-receptors and the various signaling molecules and raft-associated molecules required for their activity. Finally, we have identified several new and novel chemokine receptor antagonists that block several receptors and are capable of blocking HIV infectivity and binding as well as chemokine function. Recently, we have identified novel antagonists that appear to binding to and block several chemokine receptors and the growth hormone secretagogue receptor. These antagonists not only block chemokine binding and function but also have an impact on HIV-1 infectivity. We believe these antagonists may have potential therapeutic value in the treatment of AIDS. Overall, these studies should provide invaluable information in chemokine biology and HIV-1 infectivity and pathogenesis.